JPH06502429A - Transdermal contraceptive preparations, methods and devices - Google Patents

Abstract

The present invention provides compositions and methods for the transdermal administration of a contraceptively effective amount of a synthetic 19-nor-progesterone (ST-1435) and an estrogen, in combination, together with a suitable permeation enhancer.

Description

[Detailed description of the invention] Fertility methods and devices R league Ω Kono The present invention relates to transdermal drug administration. More particularly, the invention relates to contraceptive administration; Even more particularly, but not limited to, this R specification refers to contraceptive effective rate. 5T-1435 and estrogens such as ethinyl estradiol at For transdermal administration in combination with

R Chewing Example Background The transdermal route of parenteral administration of drugs offers many advantages and Transdermal delivery systems are described in U.S. Pat. 4.379.454, 4.286.592, 4.314.557 and No. 4.568.343, all of which are incorporated herein by reference. Relevant as a reference.

5T-1435 is a known synthetic 19-true progesterone (16-methylene-1 7α-acetoxy-19-true 4-pregnene-3,20-dione).

5T-1435 is highly potent when administered parenterally in both animals and humans. Although large, it is practically inert when administered orally. For this purpose, 5T-14 No. 35 is used as a subcutaneous implant.

Oral combination pills, implants and intrauterine devices for contraceptive purposes are, for example, inconvenient. There is sufficient knowledge regarding these issues, such as sterilization and side effects. Here Transdermal administration of contraceptives, as disclosed, attempts to eliminate or alleviate such problems. It is something.

However, there are many factors that influence the suitability of active agents for transdermal administration. . These are discussed in “Two Problems and Possibilities of Transdermal Drug Administration” by Knepp et al. at Drug Delivery: Problems and Po5sib ilities)-, CRCCrltical Revies in Ther apeutic Drug Carrier Systems, Volume 4, Issue 1 If it is desired to administer a practical drug containing a particular combination of drugs, kabIe) The problems associated with obtaining multi-drug transdermal devices are even more It can become complex and difficult and often prove insurmountable.

Common dosage forms, such as tablets or injections, contain 2 to 4 or more active agents each. The combination of each agent contained in the dosage form in their appropriate dosage ) can be administered by simply selecting the appropriate amount. However, transdermal administration For devices, the total dose of each drug is determined by the amount of each drug contained in the device. Not done. Instead, the total dose of each drug is determined by its average dermal administration rate (μg/hour). ) and the device application time, which is the average dose of drug from a transdermal delivery device. Speed is primarily determined by a combination of factors other than the amount of drug present in the device be done.

Transdermal delivery devices deliver two or more drugs at the same time from a common reservoir. The relative permeability of each drug through the skin allows for administration over the same period of time. The nature and components of the device are determined by their relative dosage or administration. 1stration) must have the same relationship with velocity. Therefore, for example , if the dosage of each drug is the same, for example 15 μg/day, then each drug is It must have the same degeneracy. However, administering one drug at 20 μg/day However, if another drug should be administered at 1 μg for 7 days, the degeneracy of one drug is It must be 20 times more degenerate than the other.

The situation becomes even more complicated if agents are required. For only one drug selectively increases skin permeability to drugs, or skin permeability to two or more drugs Identifying permeation enhancers that have the ability to relatively enhance could often present insurmountable obstacles to drug combinations.

problems associated with obtaining favorable relative rates of administration of individual drugs to the skin. Even if it can be resolved, other factors remain to be dealt with. drugs individually , or in combination with each other or with permeation enhancers, for local administration under occlusion. When used, it must not cause undue irritation or sensitization. does not stimulate individuals or non-sensitizing substances may be irritating or irritating when administered to the skin in combination with each other. may become sensitizing.

Additionally, the skin is recognized as the body's largest metabolic organ, larger than the liver. . A. Pannatier et al., “Skin as a drug-metabolizing organ (The 5ki n as a Drug Metabolizing Organ)', Dru g Metabolism Reviews, Volume 8, No. 2, pp. 319-343 ( (1978). The skin considers drugs administered transdermally to be inert or harmful. can be metabolized into metabolites that can be obtained. Therefore, each drug is metabolized by the skin. of each drug into the bloodstream at the desired rate of administration. It is necessary not to interfere with safe and therapeutically effective transdermal administration.

Assuming that these obstacles can be overcome, the drug binding capacity of the skin for each drug ( agent binding capacity) have an appropriate relationship. 1 is required. Transdermal administration of drug into the bloodstream can be initiated at steady state rates. The drug binding capacity of the skin beneath the device must be saturated before stomach. The time required to reach this steady state speed is known as the “lag time”. It is a function of the rate at which a drug penetrates into the skin and the skin's binding capacity for that drug. . In order for the 1-hour delay for both drugs to be the same, the administration rate of each drug and the There must be an inverse relationship between the binding capacity of the skin and the binding capacity of the skin.

Thus, e.g. Although many combinations of effective drugs exist, specific combinations of these or other drugs It is by no means obvious that combinations can also be safely and effectively administered transdermally.

, U.S. Patent No. 4,816,258, discloses that ethinyl estradiol and levonorges Discloses a transdermal administration system for administering Torel with a permeation enhancer as a contraceptive. Ru. Levonorgestrel is known to be immediately active when taken orally. However, if levonorgestrel -1, such as glycerol monooleate, drug from the transdermal system of reasonable or acceptable size, even in the presence of permeation enhancers. cross the human epidermis in vivo sufficiently to lead to contraceptive effective levels of It has now been determined by the inventor that this does not occur.

When 5T-1435 is administered transdermally, it shows very different effects than levonorgestrel. It is now known that this works. 5T-1435 is orally inactive When administered transdermally, its flux is determined to be effective from a system of reasonable size. levonorgestretin, which produces contraception and is sufficient to produce blood drug levels in one dose. In clear contrast to levonorgestrel, there was a significant increase in unexpectedly high flow rate.

Australian Patent No. AU-A-15323/88 describes the treatment of menopausal syndromes (menopause). Estrogen is used to treat withdrawal symptoms (associated with estrogen deficiency). A transdermal delivery system for administering synthetic gestogens and synthetic gestrogens is disclosed. This patent includes e.g. For example, natural gestogens such as progesterone can be applied using a normal-sized transdermal system. Synthetic gestodene does not pass through the skin in sufficient quantities to have a significant therapeutic effect. It is generally stated that it has a sufficient flow rate. levonorgestrel (or d-no This patent describes synthetic gestodene that can be used in transdermal systems. Norgestrel and norethisterone-17-acetate are used in the system. It is listed as a preferred synthetic gestodene because of its properties. 5T-1435 is He is not listed as a complementary guest Ken. Here, for effective contraception, Significantly higher doses of Gestken than are needed to treat the senile syndrome, and thus drug-like It should be noted that a higher transdermal flow rate is required. mentioned earlier in this specification As such, levonol, the active enantiomer of norgestrel, is a preferred guestken. Gestrel is a contraceptive effective dose of the drug when administered transdermally from a reasonably sized system. It has been found that they do not actually grow enough flow to give In addition, Nor Ethisterone-17-acetate (as norethindrone-17-acetate) is also known and is the only drug for which actual data is described in the Australian patent. some) provide insufficient transdermal flow to produce effective contraception from a reasonably sized system. It has also been found that there is. These facts are the basis of the Australian patent. that such statements are not actually true in general and in particular in providing contraceptive efficacy. Regarding this, sufficient flow of synthetic gestodene is a persistent problem and unpredictable. It shows. Therefore, certain synthetic gestodenes may be used with or without permeation enhancers. To be effectively administered transdermally without the need for a precipitant, especially in a sufficient amount to provide contraceptive effect. What can be done is by no means obvious. Contraceptive of guestken from a reasonable size system It would be particularly desirable to be able to administer effective doses, and even more so if they were unpredictable. or it is not obvious.

U.S. Pat. No. 4,863,738 discloses suitable skin permeation enhancers for steroids. Discloses glycerol monooleate as

U.S. Pat. No. 4,746,515 discloses suitable skin permeation enhancers for steroids. Discloses glycerol monolaurate as

& Tsui no Fukiyo It is an object of the present invention to administer contraceptives by a transdermal device.

Another object of the invention is to simultaneously administer estrogen and 5T-1435 at a contraceptive effective rate. It is administered transdermally.

Another object of the present invention is to administer estrogen and 5T-1435 in combination. Another object of the present invention is to provide a method for intracutaneous administration.

Yet another object of the invention is to provide contraceptive effective rates from transdermal systems of reasonable size. co-administration of estrogen and 5T-1435.

For the above and other purposes, estrogens such as ethinyl estradiol, A contraceptive effective amount of 5T-1435, together with a skin permeation enhancing amount of an appropriate permeation enhancer, This is accomplished by the present invention, which provides a method for transdermal co-administration.

The system of the present invention is suitable for being placed in drug- and permeation enhancer-communicating relationship with a skin site. A transdermal drug delivery device comprising a matrix containing The matrix is in sufficient quantity Contains a combination of permeation enhancer, estrogen, and 5T-1435, which helps drug and permeation. Continuous co-administration of an accelerator to the skin over a period of time to produce effective contraception. Cheating. The device is a reasonable source useful for administering drugs and permeation enhancers to the human body. It is is. As used herein, "appropriate size ° is approximately 1 cm" to approximately 50 cm. A bottom surface area (in contact with the skin site) that is preferably about 5 cm" to about 25 cm" means a normal-sized device with a A device approximately 200cm in size Although this can be considered a “normal” size, such a large size Not generally accepted by women for use in contraception.

Drawing example Mazato f explanation rI! J1 is a transdermal therapeutic drug administration device that can be used according to the present invention. Figure 4 shows the infusion of 5T-1435 administered from a transdermal device according to the present invention. Vitro 6 combines 5T-1435 and levonorgestrel from a transdermal administration device. Figure 2 is a graph showing comparative in vitro transdermal fluxes.

R Tomohisa Detailed Print Tax Mei Supplied separately from other elements. In certain formulations, adhesive overlay 4 is preferred over in-line contact adhesives, such as the contact MITI layer 28 shown in FIG. stomach.

This may mean, for example, that the drug reservoir is detrimental to the adhesion of the in-line contact adhesive layer 28. containing substances (such as oil-based surfactant permeation enhancers) that give the tube a unique shape. is true. Impermeable backing layer 3 is preferably slightly larger than drug reservoir 2 In this way, the substance in the drug reservoir 2 will not adversely interact with the adhesive in the overlay 4. prevent interaction. Peelable or removable liner 5 also includes device 1 and is removed immediately before applying the device 1 to the skin.

FIG. 2 shows another embodiment of the invention, a device 10 shown placed on the skin 17. explain. In this embodiment, the transdermal therapy delivery device 10 has at least two bands 12. and 14. Obi 12 is It consists of substantially the same drug reservoir as described with respect to FIG. Band 14 is preferably Manufactured from substantially the same matrix used to form band 12 Contains a permeation enhancer layer. Band 14 contains a permeation enhancer dispersed throughout and is insoluble. substantially free of estrogen or 5-1435. From band 14 to band 12 A rate limit 6[13] is placed between the two bands to control the rate of release of the accelerator.

Rate control H (not shown) to control the rate of release of enhancer from band 12 to the skin may also optionally be used, which may be present between the skin 17 and the band 12. Wear.

Rate control** is the ability to control the rate of drug to and from the delivery device. is known in the art and has a lower permeability to the permeation enhancer than that of band 12. Manufactured from permeable, semipermeable or microporous materials that grow. Suitable substances are limited to polyethylene, polyvinyl acetate, and ethylene-vinyl acetate copolymer. Including Rimmer.

An advantage of the device illustrated in FIG. 2 is that the drug loading zone 12 extends through the entire volume of reservoir 11. rather than concentrating on the skin surface. This provides a sufficient source of permeation enhancer. Layer the impermeable backing 15 and adhesive overlay 16. Furthermore, preferred Alternatively, a peelable liner (not shown) can be desiccated prior to use as described with respect to Figure 1. It is prepared on a chair 11 and removed before applying the device 1o to the skin 17.

) In the embodiments of Figures 1 and 2, the carrier or matrix material flows out (ooz j'　ng) or has sufficient viscosity to maintain its shape without flowing. death If the matrix or carrier is a low viscosity fluid substance , known in the art from, for example, U.S. Patent No. 4.379.454 (mentioned above). The composition is comprised of an impermeable backing and a permeable or microporous skin-contact membrane. (formed in between) can be completely enclosed in a pouch or pocket.

An example of a currently preferred transdermal delivery device is illustrated in FIG. In Figure 3, the transdermal administration Vice 20 contains 5T-1'435, estrogen, and a permeation enhancer. A reservoir 22 is included. Reservoir 22 preferably contains the drug and promoter dispersed therein. This is the shape of a matrix containing 1. Reservoir 22 is for both drug and permeabilizing agent. and a backing layer 24 that is impermeable to the speed control I! 26.

In Figure 3, the reservoir 22 is sufficiently viscous to maintain its shape, e.g. formed from materials such as polymers. As the reservoir 22, for example, a water-based gel can be used. When using a low viscosity material such as sealed together around their periphery to prevent Device 2o is It adheres to the surface of the skin 17 by an in-contact adhesive layer 28. Adhesion for layer 28 The agent is compatible with either estrogen or 5T-1435 or, in particular, with permeation enhancers. nature, but should choose not to interact. Adhesive layer 28 may be optionally applied. It may contain stimulants and/or drugs. Typically along the exposed surface of adhesive layer 28 , a peelable liner (not shown) is provided to apply the device 2o to the skin F. removed before In an alternative embodiment, speed control 111[26 is not present; A reservoir 22 is inserted between the backing layer 24 and the rate control membrane 267.

Various materials suitable for manufacturing the various layers of the transdermal devices of Figures 1.2 and 3 are known in the art. The above transdermal device characteristics are known or heretofore related hereto by reference. It has been disclosed to the public.

ST-1435/Strogen/Permeation promotion matrix 1m It can be a polymer. A suitable substance is 5T-1435, estrogen It should be compatible with the pigment, permeation enhancer, and other components of the system. suitable matric Examples include, but are not limited to, natural rubber, synthetic rubber or other polymers. mineral oil or petroleum jelly. Mato The lix is preferably a polymer, more preferably an anhydrous polymer. Book A preferred embodiment according to the invention is described in U.S. Patent No. 11.144.317. of VA, preferably about 9 to 60%, particularly preferably about 28 to 60%. Ethylene selected from EVA having a FFa vinyl (VA) content within the range -Vinyl acetate (EVA) copolymer. Vinyl acetate content 40% Particularly good results are obtained with EVA grown.

In addition to 5T-1435, estrogen and permeation enhancers essential to the invention The matrix contains stabilizers, dyes, pigments, inert fillers, tackifiers, excipients, and other conventional components of transdermal delivery devices as known in the art. Kade Juru.

Estrogen, which is necessary to obtain contraceptive effect, present in the therapeutic device The amount of T-1435 is, for example, the minimum required amount of each drug: matrix, adhesive layer and , the permeability of the rapid RN membrane, if present; and the period during which the device is secured to the skin. Depends on many factors like between. The drug is released over a period longer than one day. The upper limit for the maximum amount of drug present in the device is actually do not have. The minimum amount of each drug that maintains the desired release rate over a given period of administration is determined by the requirement that there must be a sufficient amount of drug to 5T-1435 generally has a concentration above saturation, i.e., unit activity (uni t activity). The excess amount is in the system. determined by a fixed useful life. However, the drug may be unsaturated without departing from the invention. Can exist at full initial level. Estrogen is a natural estrogen17 In the case of β-estradiol, this is generally the case even with aK above saturation. It is present in Ricks. However, synthetics such as ethinyl estradiol The concentration of estrogen in the matrix is determined by the flux of estrogen through the human epidermis. The amount has been found to be proportional to the estrogen concentration in the drug reservoir, so generally The amount is below saturation.

The permeation enhancer preferably maintains a permeation-enhancing concentration of the enhancer in the reservoir throughout the expected period of administration. dispersed in the matrix at a concentration sufficient to supply the

Permeation enhancers useful in the present invention are compatible with 5T-1435 and estrogen; The skin permeability to these 2M when administered with the drug to the skin of the user Selected from compounds that strengthen. Such permeation enhancers are limited to CZ-4 alcohols, such as ethanol and Improper Tools , polyethylene glycol monolaurate, polyethylene glycol-3-laurate ruamide, dimethyllauramide, esters of fatty acids having about 10 to about 20 carbon atoms, and a total monoester content of at least 51%, and the monoester has a carbon number of 10 Monoglycerides or monoglyceride mixtures of fatty acids that are ~20 monoesters can be selected from. Fatty acids include, for example, lauric acid, myristic acid, These are stearic acid, oleic acid, linoleic acid and valmitic acid. monoglyceri Permeation enhancers include, for example, glycerol monooleate, glycerol laurate and Contains glycerol monolyl ate. In a preferred embodiment, the permeation enhancer is Liethylene glycol-3-rauramide (PEG-3-LR), glycerol Monooleate (GMO), glycerol monolylate or glycerol molyte monolaurate (GML), more preferably glycerol monooleate. be.

The contraceptive system of the present invention includes a drug formulation containing estrogen and 5T-1435. .

“The term estrogen” refers to natural 17β-estradiol, e.g. Diol-ITβ-enanthate, estradiol-17β-valerate, Stradiol-3-benzoate, estradiol-17β-undecenoate -t, estradiol-16,17-hemiscunate or estradiol - Esters of natural estrogens such as 17β-sibionate, e.g. ethinyl Estradiol, ethinyl estradiol-3-isopropylsulfonate , 17- such as Kinstrol, Mestranol or Methylestradiol. Alkylated estrogens, and e.g. diethylstilbestrol, diensto esters, such as chlorine, chromituene, chlorotrianisene or cyclophenyl. Semi-synthetic estrogen derivatives such as non-steroidal compounds with trogenic activity including both. The drug formulation of the present invention preferably contains 17β-E as the estrogen. Contains stradiol or ethinyl estradiol.

In the present invention, 5T-1435 and an ester such as ethinyl estradiol are used. in combination with trogens to increase the rate of contraceptive efficacy (i.e., the rate at which effective contraception occurs). degree) and the permeation enhancer at a permeation-enhancing rate (i.e., estrogen and 5T-1 This book is administered at a rate [) for a given period of time that increases the permeability of the administration site to both 435 and 435. The transdermal flow rate required for effective contraception as provided by the invention is ethinyl estradiation. at least 10βg/day of ol or 50βg/day of 17β-estradiol and at least 80βg of 5T-1435 per day. For 10cm” device Therefore, these daily flow values are at least 0.0 for ethinyl estradiol. 4βg/Cm2/hour or 0.0 for 17β-estradiol.　2μg/cm”/ 5T-1435 converts to at least 0.33 μg/cm’/hour. It will be done.

A preferred embodiment of the present invention is a monolith as shown in FIG. 3, for example. th) (speed side [including or not including !26), and the reservoir 22 has a weight of 50~ 90% polymer (preferably EVA), 0.01-5% estrogen (preferably preferably ethinyl estradiol), 0.1 to 20% of 5T-1435, and Contains 10-50% permeation enhancer (preferably GMO). In-line adhesive layer 28 includes an adhesive that is compatible with the permeation enhancer.

The device of the invention provides estrogen therapy for extended periods of up to 7 days or longer. 5T-1435. The skin area is Since occlusion for a period longer than 7 days will be adversely affected, 7 days This is generally the maximum time period for application of a single device. To enable mobile contraception, Drug administration must be continuous. Therefore, one device has its shelf life on the skin. Once the new device has been placed, it should be placed on a new skin area, preferably on a different skin area exchange with For example, on a 7-day device, maintenance replacement of the device with a new device every 7 days and for as long as contraception is desired. This includes continuing to exchange. Alternative methods to achieve effective contraception include Disclosed herein after applying a device containing estrogen and estrogen for a period of three weeks. However, a device containing only estrogen is applied to the IJIJ.

The transdermal therapeutic device of the present invention is described, for example, in the transdermal device patents already cited herein. It is manufactured in a manner known in the art, such as by methods described herein.

The following examples are provided to explain the present invention in detail; however, the following examples illustrate the present invention. It is in no way intended to be limiting.

Devices for Examples 1 and 2 are manufactured as follows: A. Control formulation (permeabilization (no stimulant) A control formulation containing 5T-14352% by weight in a matrix of EVA40 was It was made by dissolving 5T-1435 and EVA40 in tyrene. child The solution was poured onto the FCD/polyester release liner and allowed to evaporate. 2 pieces 5 mjl of dry material at 75°C between the FCD/polyester release liner (approximately 0.1 mm) thick. The resulting film is coated with an impermeable backing (e.g. For example, heat laminated (heat-I aminated), 16cm’ and 0.97cm” discs from this laminate. Die-cut.

B. Preparations containing permeation enhancers Various concentrations of 5T-1435 in the matrix of EVA40, various permeation enhancers [ GMO, polyethylene glycol-3-rauramide (PEG-3-LR) and GMLJ, and the formulation containing the necessary permeation enhancer concentration in methylene chloride. prepared by dissolving a The GMO used had a glycerol monooleate content of 61% and a total monooleate content of 93%. Myve ro I”1899 with stellate content and glycerol monooleic acid (“M-GMO”) (Eastman Chemical Produ cts).

C. Device drug matrix/impermeable backing containing in-line adhesive Split each laminate in half and coat each half with 3M acrylate transfer. -Adhesive MSP32589 (1,6m11; acrylic resin containing 2-5% acid functionality) laminated to adhesive (adhesive). Equilibrate each final laminate for at least 5 days before testing. to distribute the accelerator and drug into the contact adhesive. in-line adhesive When the device was tested by shielding the edges of the device with a polyester tube, , the edges of the drug reservoir were not exposed to the epidermis or solution.

Example ↓ 2.5 wt% 5T-1435 and permeation enhancer M-GMO1P at 30 wt% loading Table of human skin donors A, B, C from devices containing EG-3-LR or GML In vitro transdermal 5T-1435 flow through the skin, including in-line adhesive and without, compared to a no-accelerator control.

For each test device, remove the release liner and absorb the drug release surface immediately before use. It was placed on the stratum corneum side of a dried human epidermal disc. The edge of the device is the receptor Excess epidermis was wrapped around the device to avoid exposure to solution. covered with epidermis The Teflon device on the release rate rod Attach to the flat side of the holder using nylon net and nickel wire. Star. This rod was placed in a fixed amount of receptor solution (5% ethanol in incubation water). I made him exercise again. All receptor solution was replaced at each sampling time. Les in the water bath The temperature of the scepter solution was maintained at 37°C. Each formulation was tested twice by each skin donor. I tried it.

for 0 to 4 days (for donors A and B) or for 0 to 3 days (for donor C). Below is a summary of the results as mean transdermal 5T-1435 flux in μg/am'/hr. It is shown in the notation r.

Table■ Published by Basilba A1 Donor A Donor B Donor C None Adhesive layer First 0.55 0.55 0.16 Contains adhesive -11111 -GMO Adhesive layer First 1,30 4.10 0.70 Includes adhesive 0.94 2,75 　0.67ML Adhesive layer first 2.06 4.15 1.18 Includes adhesive 1.55 1.95 0.53PFG-3-LR Adhesive layer first 1.22 1.57 0.58 Includes adhesive 0.98 1.32 　0.28 Implementation Sumata From devices containing 30% by weight M-GMO and 5T-1435 at various loads In vitro transdermal 5T-1435 flux through the epidermis of human skin donors A, B, and C. was tested according to the method of Example 1. 0-4 days (for donors A and B) or is the average of μg/cm over 0 to 3 days (for donor ○) at 27 hours. A summary of the results as transdermal 5T-1435 flux is shown below in Table II.

Table ll 5T-143Dan1■IN Upper Woni1Δ Donor B Donor C2.6% by weight Adhesive layer First 1.30 4.10 0.70 Includes adhesive 0.94 2.75 0.674.1% by weight Adhesive layer first 1.69 4,43 1.00 Includes adhesive 1.45 3.36 0.827.8% by weight Adhesive layer First 1.84 t, 77 0.67 Contains adhesive 1. 29 0.　 64 As evident in Examples 1 and 2, MSP32586 contact adhesive In addition to the adhesive function, the release rate of 5T-1435 from the drug layer and the It also functions as a rate control membrane that controls the release rate of ethinyl estradiol. Ru. The adhesive is compatible with the permeation enhancer. That is, the accelerator is the adhesive material Does not impair adhesive properties.

Implementation bay 1 3 for administering 17β-estradiol and 5T-1435. 5T-14354% by weight of a transdermal treatment device (but not including a rate control membrane) , 17β-estradiol 2% by weight, EVA40 64% by weight, M- It was manufactured from 30% by weight of GMo. 1.6m1 of 3M adhesive MSP32589 An in-line adhesive layer was present on the skin-proximal side of the drug layer.

17β-Estra from the device through cadaveric epidermis (1 donor, n-=3) In vitro skin exposure of diol and 5T-1435 was carried out according to the method of Example 4. Measurements were taken at various time points. The in vitro average flow rate of 5T-1435 is shown in Figure 4. The average flow rate of estradiol is shown in FIG.

Harm example A '　The device manufactured as in implementation fP+3 was applied to two human subjects, and the The levels of 17β-estradiol and 5T-1435 in the serum of subjects were varied. Measured at the time point. Serum levels of 5T-1435 (as average of 2 subjects) is shown in Figure 4, and serum levels of estradiol are shown in Figure 5.

Force 1 The in vitro transdermal flow rate of ST-1435 is the in vitro transdermal flow rate of levonorgestrel. The amount was compared as shown below.

F, VA 40 matrix with 5T-1435 in excess of saturation and 30% by weight Includes Myverol 18-99 and in-line MSP32589 adhesive A transdermal device containing 5T-1435 with a drug layer was manufactured. EVA40 Matri Levonorgestrel in an amount exceeding saturation and 25% by weight of Myverol in the drink 18-99 and MSP121388 acrylate adhesive (acid functionality 2 to Levonorgestrel with an in-line adhesive layer of 13M) with 5% A transdermal device was manufactured. Each device was 1.6 cm” in size. 5T- 1435-containing device and levonorgestrel-containing device in 3 humans. was placed on the skin of each cadaveric donor. The flow rate through the epidermis of each of the two drugs (3 drugs) (as the average value of .

The results shown in Figure 6 show that levonorgestrel (L-, N0G) penetrates human cadaveric epidermis. 5T-1435 has a very low flow rate through the human cadaver epidermis. Indicates that the value is large.

Preferred implementations of the invention, especially certain versions thereof! ! Although we have explained in detail about Mr. It is to be understood that variations and modifications may be made within the spirit and scope of the specification.

13 17 1+12 FIG. 4 FIG. 6 Intermediate time (hours) international search report international search report Continuation of front page Portola Vallley, Lucero Way

Claims (13)

[Claims] 1. Composition for transdermal administration of drug formulation containing estrogen and ST-1435 a contraceptive effective amount of the drug formulation and a skin permeation promoting amount of an appropriate permeation enhancer. A composition comprising a combination of. 2. A method for transdermal administration of a drug formulation comprising estrogen and ST-1435, the method comprising: (a) administering the drug formulation to a skin surface of reasonable size at a contraceptive effective rate; sometimes at a rate that is sufficient to substantially increase the selectivity of the surface for drug formulations. A method comprising administering a suitable permeation enhancer to said surface of the skin. 3. A method of contraception for women, (a) Estrogen and ST at a contraceptive effective rate on the female skin surface of reasonable size. -1435; (b) simultaneously administering said surface to the drug formulation; a permeation enhancer suitable for that side of the skin at a rate that is sufficient to substantially increase permeability; A method comprising administering. 4. Transdermal administration of a drug formulation containing estrogen and ST-1435 at a contraceptive effective rate a device of reasonable size for (a) contraceptive efficacy of the drug formulation; a reservoir comprising a matrix containing an amount and a skin permeation enhancing amount of a suitable permeation enhancer; (b) an impermeable backing of the skin distal surface of the reservoir; and (c) an impermeable backing of the skin and the skin of the reservoir; Means for maintaining rogen, ST-1435, and permeation enhancer in a communicative relationship devices containing. 5. A device that is of a reasonable size for contraceptive women, the device comprising: (a) est A contraceptive effective amount of a drug formulation containing rogens and ST-1435 and a suitable permeation enhancer. a reservoir containing a matrix containing a skin permeation promoting amount; (b) a skin distal surface of the reservoir; an impermeable backing; and (c) a reservoir with the skin, estrogen, ST-143. 5- and the permeation enhancer - means for maintaining in communication relationship devices containing. 6. Claim 1, 2, 3, 4 or 5, wherein the estrogen is ethinyl estradiol. 5. The composition, method or device according to 5. 7. of fatty acids, wherein the permeation enhancer has a total monoester content of at least 51%. Claim 1, 2, 3, 4 or 5, which is a monoglyceride or a monoglyceride mixture. A composition, method or device as described. 8. The permeation enhancer is glycerol monooleate, glycerol monolylate, or glycerol monolaurate according to claim 1, 2, 3, 4 or 5. composition, method or device. 9. The estrogen is ethinyl estradiol and the permeation enhancer is glycerol. The composition, method or method according to claim 1, 2, 3, 4 or 5, wherein device. 10. Estrogen is ethinyl estradiol and ethinyl estradiol is administered through the skin at a rate of at least 10 μg/day over a period of time. 6. A method or device according to claim 2, 3, 4 or 5. 11. ST-1435 is administered at a rate of at least 80 μg/day over a period of time. 6. A method or device according to claim 2, 3, 4 or 5, wherein the method or device is administered through the skin. 12. The estrogen is ethinyl estradiol and the permeation enhancer is glycerol. vinyl acetate and the matrix has from about 9 to about 60% vinyl acetate. 6. A device according to claim 4 or 5, comprising an ethylene-vinyl acetate copolymer. 13. A means for maintaining the reservoir against the skin is in-lined on the posterior surface of the reservoir next to the skin. 13. The device of claim 12, comprising an adhesive layer.